Diabetes causes lower extremity problems in a large number of diabetic patients. Peripheral arterial disease (PAD) can affect up to 29% of all diabetic patients while functional changes in the microcirculation are present in the vast majority of them. These abnormalities in combination with the presence of peripheral neuropathy, both somatic and autonomic, are responsible for the development of foot ulceration which currently results in more than 80,000 lower extremity amputations per year. Thus, in contrast to the non-diabetic state where pathology in the lower extremity is mainly confined in the large arteries, the pathology in diabetes is more widespread, affecting the microcirculation and the peripheral nervous system. The final outcome is an accentuated end-organ dysfunction, mainly at the local skin and muscle level. Currently, there are no techniques available that can evaluate the progression of diabetic lower extremity disease and the outcome of various therapeutic interventions. As a result, the impact of peripheral neuropathy and microvascular disease is largely ignored, leading to inadequate assessment of the severity of the disease. The primary hypothesis is that Magnetic Resonance Spectroscopic (MRS) and Blood Oxygenation Level-Dependent (BOLD) measurements will be able to satisfactorily identify changes in lower extremity muscle energy reserves and tissue hypoxia. The main aim of the current proposal is to develop new techniques that will evaluate the effect of diabetes, peripheral neuropathy and vascular disease in the muscle function of the lower extremity at the mid-calf level both during resting conditions and during graded exercise. We will also evaluate changes in muscle energy reserves over a 18-month period in diabetic patients with PAD and diabetic patients without PAD and/or neuropathy. In order to achieve our goal, we will employ a 3 Tesla MRI to assess the muscle metabolism through MRS studies of the phosphorous metabolites and the muscle oxygenation using the BOLD technique. PUBLIC HEALTH RELEVANCE: In the present study, we propose to employ Magnetic Resonance Spectroscopic (MRS) and blood oxygenation level-dependent (BOLD) measurements to measure changes in the calf muscles of diabetic patients with and without peripheral arterial disease. We believe that this project has the potential to develop a new technique that can evaluate the end-organ impact of diabetes and vascular disease in the lower extremity muscle function. A technique like this can be used in both clinical practice and the conduct of therapeutic trials.